Inhibition of monoamine oxidases A and B by simple isoquinoline alkaloids: racemic and optically active 1,2,3,4-tetrahydro-, 3,4-dihydro-, and fully aromatic isoquinolines.
A series of 1,2,3,4-tetrahydro-, 3,4-dihydro-, and fully aromatic isoquinolines were tested as substrates and/or inactivators of highly purified human monoamine oxidase A and B (MAO A and B). None were found to be a substrate for either enzyme, but many of these isoquinolines could selectively inhibit either MAO A or B. Stereoselective competitive inhibition of MAO A was found with the R enantiomer of all the stereoisomers tested, including salsolinol (Ki = 31 microM), salsoline (Ki = 77 microM), salsolidine (Ki = 6 microM), and carnegine (Ki = 2 microM). As a class, the 3,4-dihydro-isoquinolines were the most potent inhibitors tested (Ki = 2-130 microM), and the fully aromatic isoquinolines had intermediate activity (Ki = 17-130 microM) against MAO A. In contrast, only a few of these compounds markedly inhibited MAO B. 1,2,3,4-Tetrahydroisoquinoline, its 2-methyl derivative, and o-methylcorypalline gave apparent Ki values of 15, 1, and 29 microM, respectively, and two 3,4-dihydroisoquinolines (compounds 22 and 25) showed substantial inhibition of MAO B (Ki = 76 and 15 microM, respectively). These results support the concept that the topography of the inhibitor binding site differs in MAO A and B.
Bembenek
M E
ME
Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin 78712-1074.
Abell
C W
CW
Chrisey
L A
LA
Rozwadowska
M D
MD
Gessner
W
W
Brossi
A
A
D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors; D010920:Placenta / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000470:Alkaloids; D007546:Isoquinolines; D008996:Monoamine Oxidase Inhibitors